Cell replacement therapy is a promising potential treatment option for a wide variety of diseases. Many clinical conditions and disease states result from the lack of factor(s) produced by living cells or tissues, including, for example, diabetes, in which insulin production is inadequate; Parkinson's disease, in which dopamine production is decreased; and anemia, in which erythropoietin is deficient. Such conditions or diseases may be treated by cell/tissue implants that produce the missing or deficient factor(s).
However, many challenges remain in the field of cell replacement therapy. The viability and functionality of transplanted cells is compromised by, for example, lack of mechanical protection, lack of necessary factors, e.g. by inadequate vascularization or by inability of the vascular system to reach parts of the transplant, and anti-transplant host immune activity. Thus, there is a need for methods and devices that optimize the viability and functionality of implanted cells.
PCT Application No. PCT/MX99/00039, published as PCT Publication WO 00/35371, the entire disclosure of which is incorporated herein by this reference, discloses a device for xenotransplantation of islet-Sertoli cell mixtures. This is a device in which new capillaries are allowed to grow through a cylindrical, perforated metal mesh, which contains a non-completely occluded plastic (e.g., Teflon® or GoreTex®) plunger. An open space of approximately 1 mm is defined between the plunger and the mesh to allow for new capillaries to grow through the external wall of the device, providing a vascular bed between the plunger and the mesh. After some time (4-8 weeks), the plunger is removed and the selected cells for transplant are deposited in its stead.
The availability of a capillary bed in close proximity to the implanted cells, in an exemplary case islet cell clusters, is disclosed as promoting engraftment of the cellular transplant. Furthermore, the presence of the co-transplanted Sertoli cells is thought to confer immunoprotection/immunomodulation within the device. Sertoli cells are derived from the testis and express FasL (Fas ligand). These cells are thought to confer local immunoprotection and in the case of the testis microenvironment, to allow for prolonged survival of other cell types transplanted into the testis. Intratesticular transplantation of cells such as islets, or co-transplantation of islets with Sertoli cells has been attempted for the past two decades, with the objective of conferring immunoprotection from the immune-attack of the transplanted cells by the recipient immune system.
While the above-described approach has potential advantages, according to the system design, the implanted cells can still be recognized by the recipient's immune system as non-self, foreign live biologic tissues, and will thus be subject to an immune response that, in the case of allogeneic and especially xenogeneic or heterologous grafts, will be particularly strong. See, for example, FIG. 20. The result is that the implanted cells will be attacked as foreign tissues and even co-transplantation of Sertoli cells alone may not be sufficient to protect the therapeutic cells type. Thus, powerful systemic immunosuppression of the patient may nevertheless be required, especially in the case of transplantation between species such as pig to human. Moreover, a potential disadvantage of the above-proposed cylindrical device is that the deposited cylindrical column of cells will be too thick for the nutrients from the new capillaries to reach the more inwardly disposed cells, before the full thickness of the cellular implant will be fully vascularized by the peripheral capillary bed, so that these cells may not thrive and/or only a small portion of the implanted cells may survive until adequate re-vascularization occurs.
The host immune response may be prevented or minimized by encapsulation of the implanted cells with biocompatible, semi-permeable, immune-protective material or other materials by methods known in the art. The permeability of such materials are selected to allow cells to exchange oxygen, nutrients, and other small molecules with the host environment, but that diminish or prevent attack of the cells by large host immune system components such as immune cells and antibodies. In this regard, a variety of cell encapsulation methods are known in the art. Encapsulated cells may take the form of, for example, a macrostructure scaffold, a microcapsule, a nanocapsule, linked extruded capsules, or any combination thereof. These forms differ in many variables, including size, volume of cells contained, and strength and diffusion characteristics.
Encapsulated systems alone, however, do not provide the implanted cells with long-term mechanical or immune protection. Over time, and with exposure to peristalsis, compression, and pressure, among other physical insults, the capsules can break, degrade, or tear, exposing the implanted cells to physical damage as well as damage from the host immune system. In addition, it is difficult to sustain living cells within biocompatible materials for long periods of time. Cells that are not in proximity to oxygen and other growth factors and nutrients that are continuously delivered to vascularized tissue, such as those in central portions of the biological material, tend to become necrotic and to poison healthier cells in the periphery of the capsule.
Accordingly, it is an object of the present invention to avoid the requirement for long term systemic immunosuppression of recipients of cellular transplants, which currently limits the applicability of such procedures to the most severe cases of disease state for which the cellular therapy is indicated (e.g., hypoglycemia unawareness and labile diabetes in the case of insulin dependent diabetes).
It is also an object of the invention to provide an assembly that facilitates the addition of factors to favor engraftment and function of transplanted cells and tissues, before, during, and after re-vascularization of a biological material implant.
It is a further object of the invention to provide a receptacle for implanted biological material that favors cellular survival by providing mechanical support while (a) maximizing exposure of the transplant to new capillaries growing within and/or around the device (for example, by delivery of VEGF or VEGF pathway agonists or the use of degradable, angiogenic materials); and (b) locally delivering substances that can promote not only growth of new capillaries but also protect/enhance the implanted biological material, e.g. cells/tissues and/or products thereof (such as, e.g., anti-inflammatory, antiapoptotic products and/or growth factors such as corticosteroids (e.g., prednisolone, dexamethasone, loteprednol etabonate, flucinolone acetonide, etc.), IGF-I, IGF-II, HGF, GLP-1, Exendin-4, INGAP, lysophylline, pentoxyfilline; COX-2 inhibitors; interleukin-1 receptor antagonist peptide (IRAP), interleukin-10 (IL-10), alpha 1-antitrypsin (AAT), TGF-beta; antibodies to IL-1, interferon-gamma, and TNF-alpha; anti-tissue factor, complement inhibitors, oxygen generating, releasing (such as encapsulated peroxides), or transport-enhancing (such as perfluorocarbon PFC) products; as well as endothelial progenitor cells, stem cells, regulatory T cells Treg, or any others known to those skilled in the art, which may optionally or additionally be encapsulated.